HMG-CoA reductase inhibitors, also known as statins, are widely used drugs prescribed to treat hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. Examples of HMG-CoA reductase inhibitors are atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
Production of HMG-CoA reductase inhibitors is known and includes (bio)-chemical conversion, chromatography, crystallization extraction, fermentation and the like. Some HMG-CoA reductase inhibitors, like lovastatin, are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some, like mevastatin, pravastatin and simvastatin, are obtained by treating the fermentation products using the methods of chemical or enzymatic synthesis. Others, like atorvastatin, fluvastatin, pitavastatin and rosuvastatin, are the products of total chemical synthesis.
In several cases, production of HMG-CoA reductase inhibitors includes isolation and purification through salt formation. For example, in U.S. Pat. No. 4,319,039 and U.S. Pat. No. 4,342,767, the ammonium salt of lovastatin is isolated from the organic phase which has been extracted from the fermentation medium. In the same documents the ethylene diamine, tetramethyl ammonium, potassium and N-methylglucamine salts as well as salts of different amino acids such as L-arginine, L-lysine and L-ornithine is described. EP 65,835 discloses the preparation of the tert-octyl amine and L-ornithine salts of certain modified HMG-CoA reductase inhibitors, whereby also other salts with amines such as ammonia, amino acids or organic amines like benzyl amine, cycloheptyl amine, cyclohexyl amine, cyclopentyl amine, dibenzyl amine, dicyclohexyl amine, N,N-diethylbenzyl amine, N,N-diethylcycloheptyl amine, N,N-dimethylbenzyl amine, N,N-dimethylcyclohexyl amine, N,N-dimethylcyclopentyl amine, N-ethylcycloheptyl amine, N-ethylcyclohexyl amine, 2-ethylhexyl amine, N-ethyl-N-methylbenzyl amine, N-methylbenzyl amine, 2-methylbenzyl amine, N-methylcyclopentyl amine, N-methylpiperidine, N-methylpyrrolidine, morpholine, octyl amine, phenethyl amine, piperidine, pyrrolidine and tribenzyl amine are mentioned. U.S. Pat. No. 5,763,646 and U.S. Pat. No. 5,763,653 disclose the preparation of the cyclopropyl amine and n-butyl amine salts of lovastatin and their use in a process of chemical semi synthesis of simvastatin. U.S. Pat. No. 5,403,860 discloses amine salts of octahydronaphthalene oxime derivatives of HMG-CoA reductase inhibitors ML-236A, ML-236B, MB-530A and MB-530B. As final amine salts, dibenzyl amine, dicyclohexyl amine, D-glucosamine, morpholine, tert-octyl amine and D-phenylglycine alkyl ester salts are mentioned. WO 00/17150 describes amine salts of HMG-CoA reductase inhibitors in the process for semi synthetic preparation of HMG-CoA reductase inhibitors and the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of the HMG-CoA reductase inhibitors. WO 00/17150 mentions atorvastatin, fluvastatin, lovastatin, mevastatin, pravastatin and simvastatin as HMG-CoA reductase inhibitors on the one hand and a wide range of alkyl amines on the other hand, preferred examples of which are straight, branched or cyclic alkyl amines such as tert-amyl amine, n-butyl amine, sec-butyl amine, tert-butyl amine, cyclohexyl amine, dibutyl amine, dicyclohexyl amine, N,N′-diisopropylethylene diamine and N-methyl-cyclohexyl amine.
The first reports of amine salts of rosuvastatin are of a more recent date. For example, WO 2010/081861 describes the preparation of amine salts of rosuvastatin and their use in the preparation of the calcium salt of rosuvastatin. Amines disclosed by WO 2010/081861 include sec-butyl amine, tert-butyl amine, cycloheptyl amine and cyclopentyl amine. Other amine salts of rosuvastatin are disclosed in WO 2012/073256 (rosuvastatin salts of lysine, arginine, triethanol amine, ethanol amine, choline, epolamine, meglumine and ethylene diamine), WO 2012/063115 (rosuvastatin salts of thioureas, heterocyclic amines such as tetrahydrofurfuryl amine, azoles, amino acids, triazoles and pyridines); WO 2012/046193 (rosuvastatin salts of histidine and lysine); WO 2010/035284 (rosuvastatin salts of (S)-2-amino-3,3-dimethyl butane and (S)-(−)-α-methylbenzyl amine), WO 2001/60804 (rosuvastatin salts of ammonium, methyl ammonium, ethyl ammonium, diethanol ammonium, tri(hydroxymethyl)-methyl ammonium, benzyl ammonium, and 4-methoxybenzyl ammonium) and WO 2005/077916 (rosuvastatin salts of cyclohexyl ammonium, diisopropyl ammonium, isopropyl ammonium, dicyclohexyl ammonium, and (S)-(+)-α-methylbenzyl ammonium).
For pitavastatin, the number of disclosures of amine salts is more limited. In EP 742209 short chain (1-3) alkyl amine salts of pitavastatin are disclosed, in WO 2007/132482 the arginine salt is disclosed while WO 2012/106584 discloses diethanol amine and meglumine salts of pitavastatin.
Driven by the pressure to avail medication such as HMG-CoA reductase inhibitors at affordable prices, industry is in constant need for process rationalization and optimization. There is thus a need for starting substances and intermediates that are of high purity that can be prepared using simple and low cost techniques. From this perspective, it is an aim of the invention to provide alternative amine salts of HMG-CoA reductase inhibitors that can be used in the production of HMG-CoA reductase inhibitors.